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PULMONARY PATHOLOGY V Acute Lung Injury
Nils Lambrecht, MD, PhD November 16th, 2015
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READING ASSIGNMENT Robbins Basic Pathology 9th Edition
Pp – ARDS PP – Neonatal RDS Pathoma 2015 Edition:
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Pulmonary 5 – Acute Lung Injury INTEGRATION REPORT
ANATOMY: Lungs (Wiki) 10/16/14 HISTO: Respiratory Podcast 1/12/15 PHYSIO: Blood Gases (Longmuir) 1/23/15 PHYSIO: Lung mechanics- surfactant (Longmuir) 1/16/15
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Objectives 1. Learn pulmonary anatomy and histology
2. Define atelectasis a. Resorption (obstructive) atelectasis b. Compression atelectasis c. Contraction atelectasis 3. Define pulmonary edema a. Hemodynamic pulmonary edema b. Edema caused by microvascular injury 4. Define acute (non-vascular and non-infectious) lung injury a. Acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD) b. Respiratory distress syndrome (RDS) of newborn c. Acute Interstitial Pneumonitis (Hamman–Rich syndrome) d. Diffuse alveolar hemorrhage syndromes - Goodpasture syndrome - Idiopathic pulmonary hemosiderosis - Pulmonary angiitis (Wegners granulomatosis)
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The 10 leading causes of death
Significance The 10 leading causes of death
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Lung Anatomy (I)
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Lung Anatomy (II)
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Lung Histology (I)
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Lung Histology (II)
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Atelectasis Incomplete expansion (neonatal atelectasis) or collapse of previously inflated lung, which is reversible.
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Occurs when an obstruction prevents air from reaching distal airways:
Mucus Aspiration Tumor Enlarged peribronchial lymph nodes Associated with accumulation of fluid, blood, or air within the pleural cavity, which mechanically collapses the adjacent lung. Local or generalized fibrotic changes in the lung or pleura hamper expansion
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Poll Everywhere: Question 1
Which of the following is true regarding compression atelectasis? The mediastinum shifts toward the affected lung. A pneumothorax may cause this type of atelectasis A mucus plug in the bronchus may cause this type of atelectasis The typical histologic picture is edema fluid filling the alveolar spaces Diffuse fibrosis of lung parenchyma is the most common cause of this type of atelectasis
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Fluid accumulation in the air spaces of the lungs
Pulmonary edema Fluid accumulation in the air spaces of the lungs
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Intra-alveolar hemorrhage
Red blood cell accumulation in the air spaces of the lungs
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Pulmonary edema/hemorrhage
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Pulmonary edema 4A
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Intra-alveolar hemorrhage
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Hemosiderin-laden macrophages (heart failure cells)
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Pulmonary edema HEMODYNAMIC EDEMA EDEMA DUE TO MICROVASCULAR INJURY
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Hemodynamic edema Increased pulmonary venous pressure (common)
Left-sided heart failure Volume overload Pulmonary venous obstruction (mediastinal tumor) Decreased oncotic pressure (less common) Hypoalbuminemia due to: Malnutrition Liver disease (decreased protein synthesis) Nephrotic syndrome (increased protein loss) Protein losing enteropathy
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Edema due to microvascular injury
Leakage of fluid and proteins into the interstitial space and alveoli Pulmonary hydrostatic pressure is not elevated! Due to: Infections Inhaled gases Liquid aspiration Drugs & chemicals Shock, trauma Radiation Transfusion related
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Question 2 Edema associated with left sided congestive heart failure:
is due to increased hydrostatic pressure in the alveolar capillaries. causes hyaline membranes to form. is more pronounced in the upper lobes results in collapse of alveoli is a result of microvascular injury
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Adult Respiratory Distress Syndrome (ARDS)
Clinical syndrome of acute onset of severe respiratory distress with cyanosis & hypoxemia Refractory to O2 therapy X-ray Diffuse infiltrate Diffuse alveolar damage (DAD) is the histological manifestation of ARDS Decreased lung compliance No evidence of left-sided cardiac failure
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ARDS Etiology >50% cases of ARDS: Sepsis
Diffuse pulmonary infections Gastric aspiration Mechanical trauma including head injury
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ARDS Etiology Direct effects Systemic effects Aspiration Trauma
Gastric contents Sepsis Hydrocarbons Acute pancreatitis Salt or fresh water Multiple transfusions Pulmonary infections Burns Bacterial (gram positive and Cardiopulmonary bypass gram negative) Reperfusion after lung transplant Fungal Granulocytic leukemia Mycobacterial Drug exposure Viral Heroin Mycoplasmal Methadone Pneumocystic Acetylsalicyclic acid Inhalation Placidyl NO2, Cl2, SO2, NH2, O2 Paraquat Smoke DIC Fat embolism Uremia Pulmonary contusion
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Pathogenesis of ARDS Imbalance of pro-inflammatory & anti-inflammatory mediators Pulmonary macrophages increase IL-8, IL-1& TNF synthesis endothelial activation, sequestration and activation of neutrophils NEUTROPHILS ARE THOUGHT TO HAVE AN IMPORTANT ROLE IN THE PATHOGENESIS OF ARDS Activated neutrophils damage epithelium & endothelium vascular leakiness & loss of surfactant Fibrin secretion Hyaline membranes
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Clinical course of ARDS
Early or acute or exudative phase: First week (85% within 72 hrs), mortality is about 26-58% Late or proliferative phase: More than 1-2 weeks up to one year Death due to progressive fibrosis in 40% of patients Sequelae: Decreased lung function due to interstitial fibrosis (restrictive lung disease, 80% of patients) Cognitive, psychiatric abnormalities (30-50% of patients) Physical weakness (50-60% of patients)
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Acute (exudative) phase
Profound dyspnea & tachypnea Increasing cyanosis and hypoxemia Diffuse bilateral infiltrates on X-Ray
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Normal Acute Congestive phase
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Diffuse Alveolar Damage
Edema
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Congestion
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Hyeline membranes: fibrin rich edema fluid + remnants of necrotic epithelial cells
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Late or proliferative phase
Resorption of exudate and removal of dead cells by macrophages Release of TGFβ and PDGF and replacement by: Fibrosis Epithelium Proliferation of type II pneumocytes Bronchoalveolar stem cells Endothelium Migration from adjacent capillaries Marrow-derived endothelial progenitor cells
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Interstitial fibrosis
Type II pneumocyte proliferation Residual hyaline membranes
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Organizing phase Acute phase
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Fibro-proliferation in ARDS
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Advanced Interstitial Fibrosis “Honeycomb Lung”
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Advanced Interstitial Fibrosis “Honeycomb Lung”
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Neonatal Respiratory Distress Syndrome (NRDS)
Affects about 1% of newborn infants. Is the leading cause of death in preterm infants. Is histologically characterized by hyaline membranes covering the alveolar walls.
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NRDS Presentation Preterm infant, appropriate for gestational age
Usually male, delivered by cesarean section & associated with maternal diabetes Require resuscitation at birth normal color established within 30 minutes difficulty breathing and cyanosis Chest X-ray ground-glass picture Difficult to treat If the baby survives for 3-4 days excellent chance of recovery
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NRDS Etiology Incidence of NRDS is inversely proportional to gestational age (60% < 28 weeks; 30% between weeks; <5% in >34 weeks Surfactant production accelerated after 35th week gestation in fetus High inspiratory pressures required at first breath 40% of residual air volume retained after first breath with normal surfactant Surfactant deficiency collapse of lung after each breath infant works equally hard with each breath Progressive collapse & reduced lung compliance
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NRDS Risk factors Infants of diabetic mothers:
maternal hyperglycemia → compensatory fetal hyperinsulinemia → reduced surfactant synthesis Infants born with cesarean section: Labor increases surfactant synthesis Conditions associated with intrauterine stress Increased surfactant synthesis lower risk of RDS
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Fundamental defect is deficiency of pulmonary surfactant
NRDS Cause Fundamental defect is deficiency of pulmonary surfactant
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NRDS Pulmonary surfactant (I)
complex mixture of phospholipids synthesized & secreted by type 2 alveolar cells. present at the air-liquid interface of alveolar lining layer
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NRDS Pulmonary surfactant (II)
90% phospholipids & 10% proteins 1) Phospholipids Phosphatidyl choline principle component Phosphatidyl glycerol 2) Proteins SP-A, hydrophilic SP-B, hydrophobic SP-C, hydrophobic SP-D, hydrophilic
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NRDS Pulmonary surfactant (III)
Phosphatidyl choline & Phosphatidyl glycerol are absolute requirements for surfactant function SP-B and SP-C are hydrophobic and may be needed to carry phosholipid molecules to air liquid interface Mutations of SP-B & SP-C genes severe respiratory failure SP-A and SP-D are hydrophilic; bind microbial surface antigens and act as opsonins
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NRDS Pathophysiology
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NRDS Prognosis Maturity and birth weight
Promptness of institution of therapy
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NRDS Diagnosis and prevention
Analysis of amniotic fluid phospholipids good estimate of surfactant level in fetal lung Prevention: Inducing maturation in fetus at risk Prophylactic administration of surfactant to premature infants Antenatal corticosteroids administration After birth: Surfactant replacement therapy Oxygen
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NRDS Complications (I)
Retrolental fibroplasia (retina is incompletely vascularized due to oxygen therapy) decrease in VEGF endothelial cell apoptosis retinal tissue ischemic retinal scarring scar tissue can pull the retina off the back of eye retinal detachment visual impairment
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NRDS Complications (II)
Bronchopulmonary dysplasia (BPD) due to oxygen therapy Hyperoxemia, hyperventilation, prematurity, inflammatory cytokines & vascular mal-development Defined clinically as oxygen dependence to 28 days post-natally Oxygen delivery under high pressures necrotizing bronchiolitis and alveolar septal injury Recent years milder injury arrest of lung maturation in the saccular stage of development (simplified acini)
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Question 3 All of the following are true about hyaline membrane disease of the newborn is true EXCEPT: It is most common in neonates less than 32 weeks gestational age It can be prevented by administration of corticosteroids to the mother during gestation It is characterized microscopically by dense eosinophilic proteinaceous material along the inner walls of the alveolar spaces It is due to increased surfactant production by the lung Oxygen therapy for hyaline membrane disease of the newborn may lead to bronchopulmonary dysplasia
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Acute Interstitial Pneumonitis or Hamman–Rich syndrome
ARDS with interstitial lung disease in previously healthy patients Older than 40 years of age, no sex predilection Unknown cause, rapid progression to acute respiratory failure. Mortality of 33% to 74% Most deaths occur within 1-2 months Substantial fraction of patients develop recurrent ALI
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Diffuse alveolar hemorrhage Goodpasture syndrome
Proliferative, usually rapidly progressive glomerulonephritis with acute hemorrhagic interstitial pneumonitis Antibodies against α3 chain of collagen IV Diffuse alveolar hemorrhage with focal necrosis of alveolar walls, intra-alveolar hemorrhages, fibrous thickening of the septa, and type II pneumocyte hyperplasia. Linear pattern of immunoglobulin deposition (usually IgG, sometimes IgA) in alveolar walls
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Diffuse intra-alveolar hemorrhage with hemosiderin-laden macrophages
Iron stain Robbins and Cotran Pathologic Basis of Disease, 9th ed.
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Diffuse alveolar hemorrhage Idiopathic pulmonary hemosiderosis
Rare disease of immune-mediated but unknown etiology that has pulmonary manifestations and histologic features similar to Goodpasture syndrome but without renal manifestation or circulating antibodies
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Diffuse alveolar hemorrhage Pulmonary angiitis (Wegener Granulomatosis)
Bilateral acute pneumonitis with nodules and cavitary lesions Combination of small vessel necrotizing vasculitis (angiitis) and necrotizing granulomatous inflammation PR3-ANCAs are present in close to 95% of cases chronic sinusitis (90%), mucosal ulcerations of the nasopharynx (75%), and renal disease (80%)
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Wegener granulomatosis
Vasculitis of a small artery with adjacent granulomatous inflammation including giant cells large nodular cavitating lesions Robbins and Cotran Pathologic Basis of Disease, 9th ed.
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